Our overall theme and objective of this Center is to develop new classes of host-targeting antiviral therapeutics that are capable of treating multiple NIAID Emerging and Re-emerging Priority Pathogen viruses, when used alone or in combination with other available agents. The range of planned activities spans the translational development spectrum: from generating new host target focused leads, to validating promising lead molecules, and advancing optimized leads. We hypothesize that a collection of exciting preliminary datasets now offer the potential to be collaboratively translated into the development of novel broad spectrum antivirals. More specifically, we will test the following hypotheses: 1) human haploid genetic screens can identify novel host genes required for multiple RNA viruses, and recombinant AAV viral vectors can both validate these targets and serve as development candidates against the identified genes; 2) a suite of novel computational methods can identify compounds with affinity for dominant drug targets and thereby yield new antiviral therapies based on poisoning essential oligomeric viral or viral-host protein complexes; 3) recent insights into the mechanistic basis of how interferons engage their receptors and transduce their antiviral gene expression program can be leveraged into the development of interferons with novel antiviral properties, and that a unique small molecule inhibitor of PDE12 2' phosphodiesterase (A-74528) can prolong the antiviral programs generated by both these novel and currently approved interferons (IFNs); 4) the apparent widespread dependence of RNA viruses on specific intracellular pools of phosphoinositides such as PI4P and PI4,5 bisphosphate (PIP2) can be translated into an effective host cell based antiviral therapy via the development of appropriate small molecule inhibitors of specific PI4- and PIP5- kinases; 5) the development of novel countermeasures against RNA viruses can be accelerated through repurposing of existing approved drugs, and that the same type of meta-analysis of high throughput (HT) molecular measurements that has uncovered new opportunities for treating transplant rejection and fatty liver can be applied to infectious diseases and thereby yield a pipeline for identifying novel host targets upon which viruses depend and that can be inhibited with approved drugs; 6) the therapeutics contemplated above can be used in combination to achieve still more potent, broad-spectrum antiviral therapies with high barriers to resistance